JP2019129979A - Tubular artificial organ - Google Patents

Abstract

To provide a tubular artificial organ having predetermined strength to hold a lumen without increasing a wall thickness of a tube wall, which is excellent in biocompatibility and growth properties.SOLUTION: A tubular artificial organ 1A includes a tubular tissue body 10 composed of fibrotic tissues, which is formed under an environment where a biological tissue material exists, and a tubular reinforcement body 20A composed of a biodegradable material, which is included in the tubular tissue body 10. The tubular tissue body 10 is formed into a tubular shape by implanting a mold in a living body, and the tubular reinforcement body 20A is included over the entire length. The tubular tissue body 10 is composed of a biodegradable material into a mesh shape.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a high-strength tubular artificial organ that is excellent in biocompatibility and does not collapse the lumen, and a substrate used for the production thereof.

  Regenerative medicine for transplanting artificial materials and artificial organs formed by cells and treatment of congenital diseases and regeneration of tissues and organs lost in diseases and accidents as tissue regeneration scaffold materials Many studies have been used.

  Conventionally, a biological reaction called encapsulation is known as one of the self-defense functions of a living body. Encapsulation is a fibrous tissue composed mainly of fibroblasts and collagen produced by fibroblasts when, for example, a foreign body enters a deep position in the body and fibroblasts gather around the foreign body. This is a biological reaction that isolates foreign matter in the body by forming a capsule and covering the foreign matter.

  As regenerative medical technology using this encapsulation, Patent Document 1 discloses that a core rod made of a non-absorbable and non-degradable material such as silicon resin or vinyl chloride resin is implanted in a living body for a certain period of time. There has been proposed a technique for obtaining an artificial blood vessel composed of fibrous tissue by taking out an encapsulated core rod and removing the core rod. Since this artificial blood vessel is composed of only living tissue, it has excellent biocompatibility. In addition, since this artificial blood vessel is infiltrated from surrounding tissues after transplantation, self-organization proceeds, and the fibrous tissue is replaced by the recipient's vascular tissue. It also has the growth potential of being able to follow the increase.

  By the way, since the above-mentioned artificial blood vessel is composed of a fibrous tissue, shape retention is poor, and anastomosis with the blood vessel is difficult. In order to solve this, Patent Document 2 proposes an artificial blood vessel in which an anastomosis with a blood vessel is facilitated by reinforcing both ends with a sponge-like thermoplastic resin in an artificial blood vessel obtained by utilizing encapsulation. ing.

  Further, Patent Document 3 discloses that a cylindrical member and a core rod are embedded by implanting a mold composed of a cylindrical member having a slit and a core rod inserted into the cylindrical member under the skin of a living body. There has been proposed a technique for obtaining a tubular fibrous tissue body (tubular artificial organ) having an arbitrary thickness by infiltrating a fibrous tissue into a gap.

JP 2004-261260 A Japanese Patent No. 4484545 JP 2017-113051 A

  As described above, since a tubular artificial organ composed of a fibrous tissue body has poor physical strength, reinforcement may be required by some means in order to retain the lumen. As described in Patent Document 2, it is difficult to hold the lumen outside the both ends only by reinforcing both ends of the artificial blood vessel. Moreover, the method of increasing the wall thickness of a pipe wall over the full length using the technique of patent document 3 is also considered. However, if the wall thickness is increased in order to obtain a predetermined strength capable of holding the lumen, it may be larger than the wall thickness of the tube wall of the patient's tubular organ, and may not be transplanted due to anastomosis mismatch. .

  Therefore, the present invention provides a tubular artificial organ having a predetermined strength capable of holding a lumen without increasing the wall thickness of the tube wall and excellent in biocompatibility and growth and a tubular artificial organ. It aims at providing the base material used.

  The present inventors put a tubular reinforcing body made of a biodegradable material on a rod-shaped core material used as a mold, implant it in a living body, and take it out after a certain period of time, thereby removing the biodegradable tubular reinforcing body. The present inventors have found that a tubular artificial organ composed of a fibrous tissue encapsulating can be produced.

  The present invention includes a tubular tissue body that is formed in an environment where a biological tissue material exists and is composed of a fibrous tissue, and a tubular reinforcement body that is composed of a biodegradable material and is included in the tubular tissue body. The present invention relates to a tubular artificial organ provided.

  Moreover, the tubular reinforcement body made of the biodegradable material has a mesh-like side surface and a through-hole so that a fibrous connective tissue infiltrates in vivo. In order to obtain a high-strength tubular artificial organ by integrating the connective tissue with the tubular reinforcing body, the mesh preferably has a large aperture ratio, and more preferably is formed in a mesh shape with biodegradable fibers.

  Moreover, it is preferable that the said tubular structure | tissue is formed in a tubular shape by implanting a casting_mold | template in the living body, and the said tubular reinforcement body is included over the full length.

  Moreover, it is preferable that the lumen holding force in the circumferential direction of the tubular artificial organ is 2.0 [N · mm] or more.

  Further, it is preferable that the tubular reinforcing body is restricted from contracting in the axial direction.

  Further, the tubular reinforcing body is formed by braiding using a plurality of biodegradable wires, and the contraction in the axial direction is restricted by joining the intersecting portions of the biodegradable wires. preferable.

  In addition, it is preferable that the tubular reinforcement body is formed by knit knitting using a biodegradable wire to restrict axial contraction.

  The present invention also provides a base material for producing an artificial tubular organ by forming a connective tissue around the body by being embedded in a living body, and has a rod-shaped core material and a plurality of slits, and stores the core material. An outer cylinder, and a cylindrical mesh member disposed in a space between the core material and the outer cylinder, wherein the core material and the outer cylinder are made of a non-biodegradable material, and the mesh The member relates to a base material for producing a tubular artificial organ composed of a biodegradable material.

  According to the present invention, since the biodegradable tubular reinforcing body is provided in the tube wall of the tubular tissue body constituted by the fibrous tissue, the predetermined lumen capable of holding the lumen without increasing the wall thickness of the tube wall. It is possible to obtain a tubular artificial organ having a high strength and excellent biocompatibility and growth.

1 is a perspective view schematically showing a tubular artificial organ according to a first embodiment of the present invention. It is a side view which shows the tubular reinforcement body in 1st Embodiment. It is a disassembled perspective view which shows the casting_mold | template used for manufacture of a tubular artificial organ. It is a side view which shows the example of the tubular reinforcement body which concerns on 2nd Embodiment of this invention. It is a figure for demonstrating the measuring method of lumen retention force and Young's modulus (compression elastic modulus). 2 is a photograph of the tubular artificial organ of Example 1. It is the photograph of the tubular artificial organ of Example 2, and the photograph of the transplanted state. It is an observation photograph from the inside and the outside of the tissue 13 weeks after the transplantation in Example 2. 2 is an observation photograph of a tissue extracted after 13 weeks from transplantation in Example 2. FIG. It is the observation photograph at the time of the transplantation of the tubular artificial organ in the comparative example 1, and the observation photograph 25 days after the transplantation.

  In the present specification and claims, the term “tubular artificial organ” refers to a luminal organ or organ substitute such as trachea, esophagus, stomach, duodenum, small intestine, large intestine, bile duct, ureter, oviduct, and blood vessel. Are artificially produced and used for transplantation.

  In addition, “biological tissue material” is a substance necessary for forming a desired biological tissue, for example, somatic cells (fibroblasts, smooth muscle cells, endothelial cells, etc.) and pluripotent stem cells. Human cells such as ES cells, iPS cells, etc., nutrients such as various proteins (collagen, elastin) and saccharides such as hyaluronic acid, and other in vivo organisms such as cell growth factors and cytokines that promote cell growth and differentiation And various physiologically active substances present in The “biological tissue material” includes materials derived from mammals such as humans, dogs, cows, pigs, goats and sheep, birds, fish and other animals, or artificial materials equivalent thereto.

  In addition, the “living body” in which the template is implanted refers to the living body (eg, extremities, shoulders) of animals (mammals such as humans, dogs, cows, pigs, goats, sheep, birds, fish, and other animals). , Subcutaneous in the back or abdomen, or embedding in the abdominal cavity).

  The “fibrous tissue” refers to a fibrous tissue mainly composed of collagen produced by fibroblasts and formed by encapsulating a foreign substance in a living body.

In addition, “encapsulation” means that fibroblasts gather around a foreign substance in a living body, and a fibrous tissue body mainly composed of fibroblasts and collagen produced by fibroblasts covers the foreign substance in the living body. A biological reaction that isolates foreign matter.
Using this encapsulation, molds of a predetermined shape made of non-absorbable and non-degradable materials such as silicon resin, vinyl chloride resin, and stainless steel are embedded in a living body that maintains sterility for a certain period of time. The fibrous tissue formed in a predetermined shape can be obtained by removing the template after planting and encapsulating the template. Hereinafter, such a tissue shaping technique is referred to as “in vivo tissue shaping technique”. Biological tissue formation can form a fibrous tissue as an artificial organ in a living body in which aseptic conditions are maintained and supply of nutrients and oxygen is ensured. In addition, when a fibrous tissue is formed in the body, immune rejection does not occur, and thus an artificial organ with high biocompatibility can be obtained.

On the other hand, when forming a fibrous tissue by culturing in an in vitro artificial environment, a series of cell manipulations (for example, cell collection, separation, differentiation, proliferation, seeding on a scaffold, mechanical load, etc. as necessary) Engraftment under appropriate conditions, etc.) must be performed under aseptic conditions, which is more laborious and costly than in the case of in vivo histogenesis.
Accordingly, in each of the embodiments described below, an artificial organ formed using in vivo tissue formation will be described.

  Hereinafter, embodiments of the present invention will be described with reference to the drawings.

<First Embodiment>
The tubular artificial organ 1A according to the first embodiment will be described with reference to FIGS.
As shown in FIG. 1, the tubular artificial organ 1A includes a tubular tissue body 10 and a tubular reinforcing body 20A.

  The tubular tissue body 10 is composed of a fibrous tissue mainly made of collagen and is formed into a cylindrical shape. This fibrous tissue is formed with a template (base material) having a predetermined shape in a living body by using a biopsy technique. By embedding, a shape corresponding to the mold is formed. The configuration of the mold will be described in detail later.

  20 A of tubular reinforcement bodies are formed in the same cylindrical shape as the tubular tissue body 10, and are provided so that it may be included in the tube wall of the tubular tissue body 10 (refer FIG. 1). The tubular reinforcing body 20A has a predetermined strength enough to hold the lumen so that the lumen of the tubular tissue body 10 is not crushed by external pressure or negative pressure.

  As shown in FIG. 2, the tubular reinforcement body 20 </ b> A is configured in a mesh shape (mesh shape), and the fibrous tissue of the tubular tissue body 10 can enter the mesh structure. Therefore, the tubular tissue body 10 and the tubular reinforcing body 20A can be brought into close contact with each other, and the strength can be imparted to the tubular tissue body 10.

Further, since the tubular reinforcing body 20A is composed of a biodegradable material that is decomposed and absorbed in the body, it is difficult for the tubular reinforcing body to remain as a foreign substance in the body after the tubular artificial organ 1A has been transplanted and a predetermined period has elapsed. Therefore, adverse effects such as inhibiting tissue regeneration are reduced, and the growth of the tubular artificial organ 1A is not hindered.
Here, the predetermined period is a period until the fibrous tissue constituting the tubular tissue body 10 is replaced with the self tissue and the tissue regeneration is completed, and the tissue regeneration is completed as a material of the tubular reinforcing body 20A. Until then, a biodegradable material that is slow to decompose and absorb in the body is preferable so as to maintain the function as a reinforcing body. As an example, when the tubular artificial organ 1A is transplanted into the trachea, it is preferable that the shape is maintained for 6 to 12 months after the transplantation, and then slowly decomposed and absorbed. The period from 6 to 12 months after transplantation is a period necessary for tissue formation with a slow regeneration rate such as cartilage constituting the trachea, and then slowly decomposes and absorbs to suppress the occurrence of excessive inflammation. be able to.

  As an example of a method for forming the tubular reinforcing body 20A, as shown in FIG. 2, a method of forming by braiding using a plurality of biodegradable wires 21 can be mentioned. By appropriately changing the type, diameter and knitting pitch P of the biodegradable wire 21, the strength of the tubular reinforcing body 20 </ b> A and the decomposition rate in the living body can be adjusted. Here, the knitting pitch P represents the size of the mesh in the axial direction, that is, the distance between the intersections formed by the intersection of the biodegradable wires 21 as shown in FIG.

  As the biodegradable material, polyester excellent in biocompatibility is preferable, and polylactic acid, polyglycolic acid, poly (ε-caprolactone), polydioxanone (polymer of trimethylene carbonate) or a copolymer thereof should be used. Can do. A fiber made of these materials can be used as the biodegradable wire 21.

In addition, these biodegradable materials have physiological activities such as growth factors and anti-inflammatory agents for the purpose of promoting tissue regeneration and suppressing inflammatory reactions after being implanted as an artificial organ. You may impregnate the medicine which has. Examples of growth factors include platelet-derived growth factor (PDGF), transforming growth factor-α (TGF-α), transforming growth factor-β (TGF-β), insulin-like growth factor (IGF), colony stimulating factor (CSF). ), Fibroblast growth factor (FGF), epidermal growth factor (EGF), insulin, platelet-derived wound healing factor (PDWHF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF), hepatocyte growth factor (HGF) and bone morphogenetic protein (BMP).
Examples of anti-inflammatory agents include cortisol, dexamethasone, betamethasone, prednisolone, triamcinolone, acetylsalicylic acid, etenzamide, diflunisal, loxobrofen, ibuprofen, indomethacin, diclofenac, meloxicam, ferden, and acetaminophen.

  Next, with reference to FIG. 3, a method for producing the tubular artificial organ 1 </ b> A by living tissue shaping will be described.

A mold 100 shown in FIG. 3 includes a silicon resin core rod 110 having a predetermined outer diameter and a stainless steel cylinder 120 as an outer cylinder having a predetermined inner diameter and provided with the core rod 110 fixed inside. Is done. The stainless steel cylinder 120 includes a main body portion 121 and a lid portion 122, and a plurality of slits are provided in the main body portion 121 so that a living tissue material can enter the gap between the core rod 110 and the cylinder 120. 123 is formed.
With the tubular reinforcing body 20A disposed between the core rod 110 and the cylinder 120, the mold 100 is implanted in a living body such as subcutaneous or abdominal cavity for a predetermined period of about 1 to 2 months.
While the mold 100 is implanted in the living body, a fibrous tissue by encapsulation is formed in the gap between the core rod 110 and the cylinder 120 from the slit 123 formed in the cylinder 120. At this time, the fibrous tissue fills the gap between the core rod 110 and the cylinder 120 in a state of entering the network structure of the tubular reinforcing body 20A.
After elapse of a predetermined period, the mold 100 is taken out from the living body, and the core rod 110 and the cylinder 120 are removed, whereby the tubular tissue body 10 having the outer diameter as the inner diameter of the cylinder 120 and the inner diameter as the outer diameter of the core rod 110 is obtained. A tubular artificial organ 1A in which a tubular reinforcement body 20A is included in the tube wall can be obtained. That is, in this embodiment, the tubular artificial organ 1A is manufactured using the core rod 110, the cylinder 120, and the tubular reinforcing body 20A disposed in the space between the core rod 110 and the cylinder 120 as a base material. .

  In the tubular artificial organ 1A according to the first embodiment described above, the fibrous tissue constituting the tubular tissue body 10 becomes a scaffold for engraftment of cells in the body after transplantation, and gradually replaces the self tissue. Therefore, when applied to an organ in the middle of growth, it has the growth ability of being able to follow the increase in tube diameter. In addition, the lumen can be maintained even when applied to a tubular organ in which negative pressure or external pressure is applied in the radial direction.

  The tubular artificial organ 1A according to the first embodiment has the following effects.

  (1) A tubular artificial organ 1A is composed of a tubular tissue body 10 composed of a fibrous tissue formed using a template 100 having a predetermined shape in an environment where a biological tissue material exists, and a biodegradable wire 21. And a tubular reinforcement body 20 </ b> A configured and enclosed in the tubular tissue body 10. Accordingly, the tubular artificial organ 1A can be formed to have a predetermined strength capable of holding the lumen without increasing the wall thickness of the tube wall of the tubular tissue body 10. Therefore, for example, the tubular artificial organ 1A can be applied to various tubular organs, such as a blood vessel having a thin tube wall, regardless of the thickness of the tube wall. Further, the tubular tissue body 10 is composed of a fibrous tissue having high biocompatibility and growth, and the tubular reinforcing body 20A is decomposed and absorbed after transplantation so that the growth of the tubular tissue body 10 is not hindered. 1A has high biocompatibility and growth. Therefore, application to organ transplantation in children can be expected.

  (2) Since the fibrous tissue of the tubular tissue body 10 can enter the network structure of the tubular reinforcement body 20A by configuring the tubular reinforcement body 20A in a mesh shape, the tubular tissue body 10 and the tubular reinforcement body 20A And can be integrated.

<Second Embodiment>
A tubular artificial organ 1B according to the second embodiment will be described with reference to FIG. The tubular artificial organ 1B of the second embodiment is different from that of the first embodiment in the configuration of the tubular reinforcing body 20B. In the description of the second embodiment, the same components are denoted by the same reference numerals, and the description thereof is omitted or simplified.

The tubular artificial organ 1B includes a tubular tissue body 10 and a tubular reinforcing body 20B.
As in the case of the first embodiment, the tubular reinforcing body 20B is formed in a mesh shape with a biodegradable material, is formed in a cylindrical shape substantially equivalent to the tubular tissue body 10, and is provided on the tube wall of the tubular tissue body 10. And having a predetermined strength capable of holding the lumen of the tubular tissue body 10. The tubular reinforcement body 20B according to the second embodiment is different from the tubular reinforcement body 20A according to the first embodiment in that axial contraction is restricted.

  FIG. 4 shows tubular reinforcement bodies 201B, 202B, and 203B, which are examples of the configuration of the tubular reinforcement body 20B in which axial contraction is restricted.

  A tubular reinforcing body 201B shown in FIG. 4A is formed into a mesh-like cylindrical shape by braiding using a plurality of biodegradable wire rods 21, and the intersecting portion between the biodegradable wire rods 21 is super-long. A plurality of joints 23 joined by sonic welding are provided. Since the biodegradable wires 21 are joined at the joint 23, contraction in the axial direction of the tubular reinforcement 201B is restricted. In addition, about the joining method, you may use heat welding, an adhesive agent, etc. other than ultrasonic welding.

  The tubular reinforcing body 202B shown in FIG. 4 (b) is formed into a mesh-like cylindrical shape by knit-knitting (also called Lilian knitting) one biodegradable wire 21. By making the tubular reinforcing body 202B into a structure in which a plurality of loops are connected by knitting, strength can be imparted against compression in the axial direction. Therefore, contraction in the axial direction of the tubular reinforcement 202B is restricted. The knit knitting represents an operation of forming one stitch by a single threading operation on a knitting needle.

  The tubular reinforcing body 203B shown in FIG. 4 (c) is formed by cutting an axially contractible cylinder made of a biodegradable material so as to have a network structure by laser or water flow. The Therefore, the axial contraction of the tubular reinforcing body 203B is restricted. As the biodegradable material, the aforementioned biodegradable material can be used.

  In addition to the example illustrated in FIG. 4, a tubular reinforcing body 20 </ b> B having a network structure and restricted in axial shrinkage may be manufactured by injection molding a thermoplastic biodegradable resin.

  Since the tubular artificial organ 1B described above is restricted in contraction in the axial direction, it is suitably applied to transplantation of a tubular organ such as a trachea in which external pressure is applied in the axial direction.

The tubular artificial organ 1B according to the second embodiment has the following effects in addition to the effects (1) and (2) described above.
(3) The tubular artificial organ 1B includes the tubular reinforcing body 20B in which axial contraction is restricted. Thereby, since it can control that tubular artificial organ 1B contracts in the direction of an axis, a lumen can be maintained better.

  (4) The tubular reinforcing body 201B is formed by braiding using a plurality of biodegradable wire rods 21 and includes a plurality of joint portions 23 in which crossing portions of the biodegradable wire rods 21 are joined. . Thereby, since shrinkage | contraction of the axial direction of the tubular reinforcement body 201B can be controlled suitably, shrinkage | contraction of the axial direction of the tubular artificial organ 1B can be controlled suitably.

  (5) The tubular reinforcement 202B is formed by knit knitting using the biodegradable wire 21, so that axial contraction is restricted. Thereby, contraction of the axial direction of the tubular artificial organ 1B can be regulated.

<Example>
Next, an example in which the configuration of the tubular artificial organ according to each embodiment of the present invention is applied to a beagle dog with an artificial trachea that requires higher strength than an artificial blood vessel or the like will be described in detail.

  Table 1 shows the configurations of the tubular reinforcing bodies of Examples 1 to 5.

(Configuration of tubular reinforcement)
The structure of the tubular reinforcement body of Examples 1-5 is demonstrated referring Table 1. FIG.
As the biodegradable wire 21, a monofilament formed by spinning and drawing poly L-lactic acid (weight average molecular weight 450,000, melting point 195 ° C.) was used, and each of them had a cylindrical shape with an inner diameter of 15 mm and a length of 40 mm. The tubular reinforcement body of Examples 1-5 was produced. The diameter of the biodegradable wire 21 is 0.3 mm in Examples 1 to 4, and 0.4 mm only in Example 5.
The tubular reinforcing bodies shown in Examples 1 and 2 are formed by braiding a plurality of biodegradable wire rods 21, and an implementation corresponding to the configuration of the tubular reinforcing body 20A according to the first embodiment. It is an example (refer FIG. 2). The tubular reinforcing bodies shown in Examples 3 to 5 are formed so that axial contraction is restricted, and the configuration of the tubular reinforcing body 20B according to the second embodiment (Example 3 is shown in FIG. The configuration of the tubular reinforcing body 201B shown in a), Examples 4 and 5 are examples corresponding to the configuration of the tubular reinforcing body 202B shown in FIG. 4B.

(Measurement method of strength)
The physical properties of the tubular reinforcement were evaluated by “Young's modulus (compression elastic modulus)” as “luminal retention strength” which is an index of strength in the radial direction and strength in the long axis direction. A compression tester (Autograph AG-X Plus, manufactured by Shimadzu Corporation) was used to measure these physical properties.
As shown in FIG. 5 (a), the lumen holding force is measured by placing the tubular reinforcement on a jig J (adjusted to the length of the tubular reinforcement) that regulates the movement in the axial direction. The compression strength was measured by pressing from above with the pusher PL until the outer diameter reached 30%. The lumen holding force [N · mm] is determined by compressive strength [N] × (diameter of tubular reinforcement) ² [mm ² ] / axial length [mm] of the tubular reinforcement.
Further, as shown in FIG. 5 (b), the axial Young's modulus is determined by placing the tubular reinforcement body vertically and pressing the tubular reinforcement body from above with a pusher PL until the length reaches 90%. The compressive strength was measured. The maximum spring constant [N / mm] was determined from the slope of the obtained stress strain curve in the 0-10% strain region. The Young's modulus E (MPa) is obtained by E = spring constant [N / mm] × initial length [mm] / cross-sectional area [mm ² ] of the tubular reinforcement.

(Measurement result of strength)
The results of measuring the lumen holding force and compression elastic modulus of the tubular reinforcements of Examples 1 to 5 and the lumen holding force of the tubular artificial organ of Comparative Example 1 will be described in detail.

As shown in Table 1, the tubular reinforcing bodies of Examples 1 to 5 all had a lumen holding force of 2.0 [N · mm] or more.
Regarding the lumen holding force, the braiding method is the same braiding, and when Example 1 having a large knitting pitch is compared with Example 2 having a small knitting pitch, Example 2 has a larger lumen holding force. Therefore, it was confirmed that the lumen retention force can be increased by reducing the knitting pitch.
Example 2 in which the knitting method is the same, the knitting pitch is the same, and the intersecting portion of the biodegradable wire 21 is not joined, and the joined Example 3 in the axial compression elastic modulus. When compared, Example 3 had a larger Young's modulus. Therefore, it was confirmed that the Young's modulus can be increased by joining the intersecting portions of the biodegradable wire rods 21 to restrict axial contraction. In addition, when Example 3 and Example 4 having different means for restricting axial contraction are compared, Example 3 in which a tubular reinforcing body is formed by braiding and the intersecting portion of the biodegradable wire 21 is joined. In comparison, it was confirmed that Example 4 formed by knit knitting can greatly improve the Young's modulus.
Further, when Example 4 and Example 5 in which the knitting method is the same knitting and only the diameter of the biodegradable wire 21 is compared, the lumen of the biodegradable wire 21 is increased by increasing the diameter. It was confirmed that the holding force and Young's modulus can be improved.

(Mold structure)
As a mold, a round rod-shaped core rod 110 made of silicon resin having an outer diameter of 15 mm and a length of 40 mm, and a stainless steel cylinder 120 having a main body portion 121 having a plurality of slits 123 and an inner diameter of 17 mm and a lid portion 122, and (See FIG. 3).

(Production of tubular artificial organs)
The tubular reinforcing body 20A of Example 1 manufactured under the conditions shown in Table 1 was inserted into the mold 100 described above.
The template 100 obtained in this way was implanted under the back of a beagle dog to perform in vivo tissue formation. In implanting the mold 100, the beagle dog was anesthetized by a general procedure, then the disinfected skin was incised about 30 mm, the sterilized mold 100 was placed subcutaneously, and the skin was sutured. After the implantation operation, water was freely given, food was given according to body weight, and beagle dogs were raised in a normal environment.
Two months after the implantation of the mold 100, the encapsulated mold 100 was removed under anesthesia, the mold 100 was removed, and the cylindrical shape of Example 1 having an inner diameter of 15 mm, an outer diameter of 17 mm, and a length of 40 mm was obtained. A tubular artificial organ 1A was obtained (see FIG. 6). The lumen holding force of the tubular artificial organ 1A was measured and found to be 2.5 N · mm. From this result, it was shown that the lumen holding force of the tubular artificial organ 1A is larger than at least 2.1 N · mm of the tubular reinforcing body 20A. The obtained tubular artificial organ 1A was decellularized by being immersed in ethanol for 24 hours or more at room temperature before transplantation.

  Moreover, the tubular artificial organ 1A of Example 2 provided with 20 A of tubular reinforcement bodies of Example 2 was obtained by the method similar to Example 1 (refer Fig.7 (a)). The obtained tubular artificial organ 1A was decellularized by being immersed in ethanol for 24 hours or more at room temperature before transplantation.

  Moreover, the tubular artificial organ 300 of the comparative example 1 which does not have a tubular reinforcement body was obtained by the method similar to Example 1 and 2 except not inserting a tubular reinforcement body using the above-mentioned casting_mold | template 100. When the lumen holding force of the tubular artificial organ 300 was measured, it was 0.1 N · mm, which was lower than the lumen holding force of the tubular artificial organ 1A of Example 1.

(Tracheal transplantation test for tubular artificial organs)
The results of a test of transplanting the tubular artificial organs of Examples 1 and 2 and Comparative Example 1 into the trachea of a beagle dog will be described.

First, the contents of the tracheal transplantation test of the tubular artificial organ 1A of Example 1 and the course after the transplantation will be described in detail.
Under general anesthesia, 1 cm of the trachea of the beagle dog was excised, and the tubular artificial organ 1A of Example 1 cut to 1 cm length was connected by end-to-end anastomosis. After transplantation, the animals were reared in the usual manner. No abnormal findings were observed during the breeding, and the respiratory condition was good.
As a result of observing the trachea of the transplanted portion with an endoscope 19 weeks after the transplantation, the patency of the lumen was maintained, but the lumen diameter was 5.5 mm. Therefore, the balloon catheter was expanded with a balloon catheter having an outer diameter of 15 mm. In addition, spraying of 1% to 2 mL of 0.1% Linderon (steroid) was performed.
As a result of observation with an endoscope again at 24 weeks after transplantation, the patency of the lumen was maintained as in the previous observation, but the lumen diameter was 6.5 mm. While expanding, spraying of 1% to 2 mL of 0.1% Linderon (steroid) was performed.
As a result of endoscopy at the 25th and 27th weeks after transplantation, the lumen diameter of the trachea was maintained at 7 mm, and the patency was maintained.

Next, the contents of the tracheal transplantation test of the tubular artificial organ 1A of Example 2 and the course after the transplantation will be described in detail.
Under general anesthesia, 2 cm of the trachea of the beagle dog was excised, and the tubular artificial organ 1A of Example 2 cut to a length of 2 cm was connected by end-to-end anastomosis (see FIG. 7B). After transplantation, the animals were reared in the usual manner.
Four weeks after transplantation, the lumen diameter of the trachea in the transplanted portion was narrowed to 5 mm, and therefore, the balloon catheter was expanded with a balloon catheter having an outer diameter of 10 mm.
Thereafter, expansion was performed with a 15 mm balloon catheter at 5, 6, and 7 weeks, and spraying of 1 mL to 2 mL of 0.1% Linderon (steroid) was performed.
Since the lumen diameter of the trachea in the transplanted portion was stable from about 8 weeks, the balloon catheter was not expanded and the steroid agent was not sprayed thereafter. It is thought that the self-organization of the tubular artificial organ 1A transplanted at 8 weeks progressed and the strength was stabilized. No other abnormal findings were observed during the breeding, and the respiratory condition was good.
The results of euthanizing 13 weeks after transplantation and observing the transplanted tubular artificial organ 1A with an endoscope are shown in FIG. 8 (a), and the results of observation with the trachea exposed through incision are shown in FIG. 8 (b). ). Further, in order to observe the anastomosis from the inside, FIG. 9A shows a photograph of a state in which a trachea including the tubular artificial organ 1A is incised, and FIG. 9B shows an enlarged photograph of FIG. 9A. .
The tubular artificial organ 1A was engrafted in the living trachea, and there was no abnormality in the anastomosis as shown in FIGS. 8 (a) and 8 (b). Further, the lumen diameter of the transplanted portion indicated by the arrow in FIG. 8A was 10 mm, and the lumen structure was maintained. Further, as shown in FIGS. 9A and 9B, a white tracheal mucosa was formed on the inner surface of the lumen, and reconstruction of the tracheal tissue was proceeding.

Finally, the contents of the tracheal transplantation test of the tubular artificial organ 300 of Comparative Example 1 and the course after the transplantation will be described in detail.
Under general anesthesia, 1 cm of the trachea of the beagle dog was excised, and the tubular artificial organ 300 of Comparative Example 1 cut to 1 cm length as shown in FIG. After transplantation, the animals were reared in the usual manner.
After transplantation, there was no abnormality in the health condition, but he died suddenly on the 25th day. As a result of necropsy, the transplanted tissue was crushed toward the lumen as shown in FIG. Thus, it was shown that the tubular artificial organ 300 that does not have the tubular reinforcement has a small lumen holding force and does not have a sufficient function as an artificial trachea.

The preferred embodiments and examples of the tubular artificial organ of the present invention have been described above, but the present invention is not limited to the above-described embodiments and examples, and can be modified as appropriate.
The present embodiment is a technique for forming a tubular tissue body that encloses a tubular biodegradable material by in vivo tissue formation. This technology can design all sizes and shapes, and enables tissue formation according to the physique and lesion. In addition to its high affinity with the living body, it has a mechanically high lumen retention, so it can also be used as an organ regeneration scaffold for organs that apply negative pressure during inspiration, such as the trachea, and for the esophagus and diaphragm. it can. After implantation, cells infiltrate from surrounding tissues and self-organization (tissue regeneration) progresses. Finally, a biodegradable skeleton is decomposed and absorbed to form a normal tissue body and have growth potential. It becomes. Therefore, it can also be used in children who need organ growth after transplantation.
In the above-described embodiments, the case where the present invention is applied to the trachea as an example of a tubular artificial organ has been described. It may be applied to organs.

DESCRIPTION OF SYMBOLS 1A, 1B Tubular artificial organ 10 Tubular structure | tissue 20A, 20B Tubular reinforcement 21 Biodegradable wire 100 Mold 110 Core rod 120 Cylinder 121 Body part 122 Cover part 123 Slit J Jig P P Knitting pitch PL Pusher

Claims (8)

A tubular tissue body formed in an environment in which a biological tissue material exists and composed of fibrous tissue;
A tubular prosthesis comprising a tubular reinforcement body made of a biodegradable material and enclosed in the tubular tissue body.   2. The tubular artificial organ according to claim 1, wherein the tubular tissue body is formed into a tubular shape by implanting a template in a living body, and the tubular reinforcing body is included over the entire length.   The tubular artificial organ according to claim 1 or 2, wherein a lumen holding force in a circumferential direction of the tubular artificial organ is 2.0 [N · mm] or more.   The tubular artificial organ according to any one of claims 1 to 3, wherein the tubular reinforcing body is configured by a biodegradable material in a mesh shape.   The tubular artificial organ according to any one of claims 1 to 4, wherein the tubular reinforcing body is restricted from contracting in an axial direction. The tubular reinforcement is formed by braiding using a plurality of biodegradable wires,
The tubular artificial organ according to claim 5, wherein contraction in the axial direction is regulated by joining crossing portions of the biodegradable wires.   The tubular artificial organ according to claim 5, wherein the tubular reinforcement body is formed by knit knitting using a biodegradable wire, thereby restricting axial contraction. A base material for producing an artificial tubular organ by forming a connective tissue around it by being embedded in a living body,
A rod-shaped core material;
An outer cylinder having a plurality of slits and storing the core material;
A cylindrical mesh member disposed in a space between the core material and the outer cylinder,
The core material and the outer cylinder are made of a non-biodegradable material,
The mesh member is a base material for producing a tubular artificial organ composed of a biodegradable material.